The invention relates to topically applicable galenic formulations which contain one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives and are suitable for the cosmetic or medicinal treatment of skin, hair and/or nails, for example for the treatment of diseases or functional disorders of human or animal skin, hair and/or nails.
The chemical name for biotin is hexahydro-2-oxiothieno [3,4-d]imidazole-4-valeric acid. Its chemical structure corresponds to the formula 
The efficacy of biotin in skin, hair and nail diseases has been assessed in different ways in the past. Although, by means of continuous biotin therapy, it was possible to show the efficacy in the case of soft, brittle and splitting nails, different forms of alopecia and atopic and seborrheic dermatitis in a detectable manner, use remained sparing, as this is associated, despite no side effects at all, with the necessity of an extended treatment period of several months (R. Bitsch et al. (1994) Biotin, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart; V. E. Colombo et al. (1990) Treatment of brittle fingernails and onychoschizia with biotin: scanning electron microscopy. J. Am. Acad. Dermatol. 23: 1127-1132; G. L. Floersheim (1989) Behandlung brxc3xcchiger Fingernxc3xa4gel mit Biotin [Treatment of brittle fingernails with biotin]. Z. Hautkr. 64: 41-48; G. L. Floersheim (1992) Prxc3xcfung der Wirkung von Biotin auf Haarausfall und Haarqualitxc3xa4t [Testing the action of biotin on hair loss and hair quality]. Z. Hautkr. 67: 246-255; W. Gehring (1996) Der Einfluss von Biotin bei reduzierter Nagelqualitxc3xa4t. Eine plazebokontrollierte doppelblinde klinische Studie [The influence of biotin on reduced nail quality. A placebo-controlled double-blind clinical study]. Akt. Dermatol. 22: 20-25; U. Siebert et al. (1996) Zur Dosierung und Wirkung von Biotin bei Nagel- und Haarwachstumsstxc3x6rungen [The dosage and action of biotin in nail and hair growth disorders]. Zeitschrift Hautnah 6: 438-443).
It is known that topically applied biotin-containing formulations having a biotin content of 0.25% and 0.50% lead to a visible reduction in the development of wrinkles on the skin of old people (L. Gilli et al. (1995) Beeinflussung der Fxc3xa4ltchenausprxc3xa4gung bei Altershaut durch topisch appliziertes Biotin [Influencing the development of wrinkles on the skin of old people by means of topically applied biotin]. Z. Hautkr. 70 (6): 419-425). In these investigations, it was not possible to show any epithelial and histopathological changes at all in the areas treated.
Regardless of the positive clinical experience with biotin, knowledge about the mechanism of action is incomplete. From the present state of knowledge, biotin, as a coenzyme, has a number of carboxylases which are linked in with various vital metabolic functions (R. Bitsch et al. (1994) Biotin. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart). In addition to its function as a coenzyme, the independent pharmacological effects of biotin, e.g. the influence on the keratin structure, are of interest for therapeutic use. The underlying mechanism of the influence on the growth and differentiation behavior of the keratinocytes, however, is controversial (A. Fritsche (1990) Biotin verxc3xa4ndert das Zytokeratinmuster von kultivierten Keratinozyten [Biotin changes the cytokeratin pattern of cultured keratinocytes], inaugural dissertation, University of Zurich; A. Fritsche et al. (1991) Pharmakologische Wirkungen von Biotin auf Epidermiszellen [Pharmacological effects of biotin on epidermal cells]. Schweiz. Arch. Tierheilk. 133: 277-283; A. Limat et al. (1996) Proliferation and differentiation of cultured human follicular keratinocytes are not influenced by biotin. Arch. Dermatol. Res. 288: 31-38).
Owing to its hydrophilic properties, biotin belongs to the substances for which the horny layer, with its lipophilicity and the low hydration in the normal state, represents a penetration barrier of particular size.
For the topic application of biotin there thus exist particular galenic requirements.
The object was thus to make available topically applicable galenic formulations which contain compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and are suitable for the cosmetic or medicinal treatment of skin, hair and/or nails.
Surprisingly, it has now been found that this object is achieved by the provision of galenic formulations comprising
a) one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and
b) one or more compounds selected from urea and urea derivatives.
The invention furthermore relates to
the use of one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and of one or more compounds selected from urea and urea derivatives for the production of a topically applicable galenic formulation,
a process for the production of a topically applicable galenic formulation, characterized in that one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives are brought into a suitable formulation form, if appropriate with further active compounds, excipients and/or vehicles.
The application of the galenic formulations according to the invention can take place both to humans and to animals. The galenic formulations according to the invention can be used both in cosmetics and in human and in veterinary medicine. The areas of use of the galenic formulations according to the invention relate to the therapy, prophylaxis and/or metaphylaxis of skin diseases, of functional disorders of the skin, of skin-ageing processes and of dry skin conditions.
The invention furthermore relates to the use of
a) one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and
b) one or more compounds selected from urea and urea derivatives
for the production of a topically applicable galenic formulation
for improving the penetration of the compounds selected from biotin, the physiologically acceptable salts of biotin, biotin esters and the stereoisomeric forms of these compounds into deeper layers of human or animal skin, mucous membrane and/or nails,
for the protection, for the maintenance and/or for the reconstruction of the normal function and structure of human or animal skin and/or for the prevention of environmentally related skin damage, for example UV-related skin damage,
for the treatment of diseases of the hair, sebaceous and/or sweat glands of human or animal skin and/or
for cosmetic skin treatment, in particular for skin care.
In particular, xe2x80x9cpenetration of biotin into deeper layers of human skinxe2x80x9d, for example, in the context of the present invention means that biotin penetrates through the horny layer of the human skin. Without a penetration enhancer, biotin does not penetrate or does not penetrate in an efficacious concentration through the horny layer of the human skin. However, it has been found, for example, that the penetration of topically applied biotin through the horny layer into human skin is improved if biotin is combined with a penetration enhancer, preferably with urea and particularly preferably with urea in an emulsion. It has been found that the combination of biotin with a penetration enhancer of this type makes possible, for example, the penetration of biotin into the living epidermis in an efficacious concentration.
In the context of the present invention, penetration enhancers are designated as substances which, for example, increase the permeability or increase the penetration of the active compounds at the site of application.
The application of the galenic formulations according to the invention make possible, for example, the penetration of biotin in adequate concentration of at least 10xe2x88x925 mol/l for the treatment of diseases of the hair, sebaceous and/or sweat glands of the skin. The use of the galenic formulations according to the invention on finger- and/or toenails makes possible, for example, the penetration of biotin in a concentration of at least 10xe2x88x925 mol/l into the deep portions of the nail and/or the nail matrix. Customarily, approximately 10 min to 24 h, for example, after topical application of the galenic formulation according to the invention to the prickle-cell layer and/or to the basal-cell layer of the skin a biotin concentration is achieved which is suitable for the stimulation of epidermal lipid synthesis and is at least 10xe2x88x925 mol/l.
Moreover, it has been found that the influence of biotin on lipid synthesis is concentration-dependent. This result is shown in FIGS. 1 to 4.
While low biotin concentrations in the medium (10xe2x88x926 mol/l) can be classified as inefficacious, the lipid synthesis power of keratinocytes could be increased at higher biotin concentrations in the medium (10xe2x88x925 to 10xe2x88x923 mol/l)
Increases in the concentration of the fatty acids myristic acid (MA), palmitic acid (PA), stearic acid (SA) and oleic acid (OA) under the action of biotin were detected both in the culture of HaCaT keratinocytes, and in native human keratinocytes. The absence of an increase in the concentration of linoleic acid (LA) is to be considered in connection with the inability of the keratinocytes to synthesize polyunsaturated fatty acids independently. The results are shown in FIGS. 1 to 4 for the action of biotin on human cultured HaCaT keratinocytes.
It has furthermore been found that the penetration of biotin into the human skin is vehicle-dependent, the penetration from the W/O vehicles being markedly lower than the penetration from the more hydrophilic O/W vehicles. However, neither standard W/O nor standard O/W vehicles which do not contain any penetration enhancer are suitable for attaining sufficiently high (epidermal biotin concentrations for stimulation of lipid synthesis. The inadequate penetration of biotin from a standard O/W vehicle which contains no penetration enhancer is shown for the horny layer in FIG. 5 and the epidermis in FIG. 6 (see values for ST O/W in FIGS. 5 and 6).
Vehicle optimization was achieved according to the invention by the addition of urea to the standard vehicle. By means of the incorporation of urea into the standard vehicle, formulations according to the invention result which bring about increased penetration of biotin into human skin. The penetration increase is dependent on the extent of the vehicle used.
For example, the use of an O/W emulsion with 10% urea according to the invention leads, even after a short duration of action of 30 min, to an effective epidermal biotin concentration. The effect was also detectable after a prolonged application period of 300 min. These results are likewise shown in FIGS. 5 and 6 (see values for U O/W in FIGS. 5 and 6).
The comparison of the biotin concentration in the dermis after penetration of biotin from a standard O/W vehicle (see values for ST O/W) and after penetration of biotin from a corresponding 10% by weight vehicle comprising urea (see values for U O/W) into human skin ex vivo is shown in FIG. 7.
The biotin concentration in the dermis after penetration of biotin from the vehicle comprising 10% by weight of urea into human skin ex vivo is markedly below 0.01 nmol/mm3 both after 30 min and after 300 min. The concentration of 0.01 nmol/mm3 corresponds to the effective biotin concentration of 10xe2x88x925 mol/l from FIG. 2. This shows that owing to the topical application of formulations according to the invention which contain urea, the penetration of biotin through the horny layer can be advantageously controlled in such a manner that the efficacious biotin concentration in the epidermis is exceeded, but remains deficient in the dermis (see FIGS. 6 and 7).
In U.S. Pat. No. 5,166,168, topically applicable formulations are described which contain biotin or a pharmaceutically acceptable salt of biotin and are suitable for the treatment of nail diseases. These formulations can contain penetration enhancers in an effective amount, for example, menthol, propylene glycol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide and azone. However, there is no information on urea or urea derivatives as penetration enhancers.
The compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds can be present in the galenic preparations, for example, as optical isomers, diastereomers or racemates.
The biotin esters are characterized by the following generic structural formula: 
According to the invention, R is a branched or unbranched alkyl group having 1 to 18 C atoms or a branched or unbranched alkenyl groups having 1 to 18 C atoms. Preferred biotin esters are those in which R is methyl or ethyl.
Among the compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds, biotin is preferred, in particular D-cis-hexahydro-2-oxothieno [3,4]d]imidazole-4-valeric acid of the formula 
Biotin can be used in the formulations according to the invention in the form of any known pharmaceutically acceptable salt. Preferred physiologically tolerable salts of biotin are, for example, alkali metal, alkaline earth metal or ammonium salts, such as Na, K, Mg or Ca salts, and also salts derived from organic bases such as ethylamine, triethylamine, ethanolamine, diethylaminoethanol, ethylenediamine, piperidine, morpholine, 2-piperidinoethanol, benzylamine and procaine.
Suitable urea derivatives, for example, are those which release urea after cleavage. Allantoin is preferred among the urea derivatives.
Urea is preferred among the compounds selected from urea and the urea derivatives.
Among the galenic formulations according to the invention, those which contain biotin and/or urea are thus preferred.
The compounds selected from urea and urea derivatives can be incorporated in different galenic formulations, such as in O/W or W/O emulsions. Urea is preferably incorporated in O/W emulsions.
The galenic formulation is prepared by bringing one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives into a suitable formulation form, if appropriate with excipients and/or vehicles. The excipients and vehicles originate from the group of carriers, preservatives and other customary excipients.
The galenic formulations based on one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives are used externally.
Use forms which may be mentioned are, for example: solutions, suspensions, emulsions, pastes, ointments, gels, creams, lotions, lakes, powders, soaps, surfactant-containing cleansing preparations, oils and sprays. In addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, any desired customary vehicles, excipients and, if appropriate, further additive compounds are added to the formulation.
The excipients and active compounds optionally contained in the galenic formulations according to the invention can be either of hydrophilic or lipophilic nature.
Preferred excipients are derived from the group consisting of the preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants and odor enhancers.
Ointments, pastes, creams and gels, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
Powders and sprays, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles, e.g. lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can additionally contain the customary propellants, e.g. chlorofluorohydrocarbons, propane/butane or dimethyl ether.
Solutions and emulsions, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles such as solvents, solubilizers and emulsifiers, e.g. water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed oil, peanut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
Suspensions, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles such as liquid diluents, e.g. water, ethanol or propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitan ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
Soaps, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles such as alkali metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolyzates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugar or mixtures of these substances.
Surfactant-containing cleansing products, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, fatty acid protein hydrolyzates, isothionates, imidazolinium derivatives, methyltaurates, sarcosinates, fatty acid amide ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol fatty acid esters or mixtures of these substances.
Face and body oils, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, can contain the customary vehicles such as synthetic oils such as fatty acid esters, fatty alcohols, silicone oils, natural oils such as vegetable oils and oily plant extracts, paraffin oils, lanolin oils or mixtures of these substances.
Preferably, the compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds, the penetration enhancers or promoters and/or the excipients are present in the galenic formulations according to the invention incorporated in colloidal carrier systems, in particular they are present incorporated in nanoparticles, liposomes or microemulsions.
Further typically galenic application forms are also lipsticks, lipcare sticks, mascara, eyeliner, eyeshadow, rouge, powder, emulsion and wax make-up, and sunscreen, pre-sun and after-sun preparations.
Preferred application forms are pastes, ointments, creams, emulsions, gels and lakes. In this context, the galenic formulation according to the invention is particularly preferably present as an O/W emulsion. The application to finger- and/or toenails is preferably carried out as a lake.
The proportion of the compound or of the compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds in the galenic formulation according to the invention is preferably from 0.05 to 5% by weight based on the total galenic formulation.
The proportion of the compound or of the compounds selected from urea and urea derivatives in the galenic formulation according to the invention is preferably from 1 to 40% by weight based on the total galenic formulation.
The galenic formulations, in addition to one or more compounds selected from biotin, the physiologically tolerable salts of biotin, biotin esters and the stereoisomeric forms of these compounds and one or more compounds selected from urea and urea derivatives, preferably contain one or more substances having free-radical scavenger properties, in particular vitamin E, vitamin C and/or their esters. The proportion of the compound or of the compounds having free-radical scavenger properties is preferably from 0.01 to 30% by weight, particularly preferably from 1 to 30% by weight, based on the total galenic formulation.
All compounds or components which can be used in the galenic formulations are either known and commercially obtainable or can be synthesized by known methods.